Dual EGFR Targeting Shows Promise in Colorectal Cancer

Cetuximab, a monoclonal antibody (mAb) that targets the epidermal growth factor receptor (EGFR), prolongs overall survival in patients with KRAS wild-type metastatic colorectal carcinoma (CRC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib, are approved for the treatment of advanced lung and pancreatic cancers but have not been as extensively studied in metastatic CRC. Because recent clinical trials have demonstrated the efficacy of targeting the related receptor tyrosine kinase HER2 with both a TKI and mAB in advanced breast cancer, Weickhardt and colleagues sought to investigate the efficacy of dual EGFR targeting in metastatic CRC. The combination of cetuximab plus erlotinib showed synergistic antiproliferative effects in vitro that were attributed to enhanced vertical blockade of the EGFR signaling pathway as well as inhibition of additional downstream targets. Based on these findings, the authors conducted an open-label, single-arm, phase II study of cetuximab plus erlotinib in 50 patients with metastatic CRC who failed chemotherapy. The overall response rate was 31%, with progression-free and overall survival durations of 4.6 and 12.1 months, respectively. No response was observed in patients whose tumors harbored KRAS, BRAF, or PIK3CA mutations. However, in the subset of patients with KRAS wild-type tumors, overall response as well as progression-free and overall survival increased to 41% and 5.6 and 12.9 months, respectively. The most commonly reported adverse event was skin toxicity, which occurred in a higher percentage of patients than is reported for single-agent EGFR mAb use, resulting in 3 patient withdrawals from the study. Although a randomized trial is needed to confirm the enhanced therapeutic efficacy of dual EGFR targeting, this study suggests that the combination of cetuximab and erlotinib may improve the clinical outcome of a subset of patients with metastatic CRC.

Weickhardt AJ, Price TJ, Chong G, Gebski V, Pavlakis N, Johns TG, et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX Study in chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol 2012 Mar 12 [Epub ahead of print].